Project Summary: Autistic disorder (autism) and other pervasive developmental disorders are neuropsychiatric developmental disorders which are increasingly being diagnosed. Despite their frequency and associated impairments which can be severe and lifelong, there have been limited controlled drug studies to date. The long-term goal of our research is to advance the science behind the pharmacologic treatment of autism and related disorders. This is especially important since there are very few treatments that have been shown to be effective for this devastating disorder. Furthermore, the response to medications is frequently quite variable and predictors of response to guide treatment have not been identified. A significant treatment challenge has been the management of severe hyperactivity when comorbid with autism. In this project, we will evaluate the efficacy and tolerability of atomoxetine for significant hyperactivity and determine pharmacogenetic predictors of response. We will accomplish this goal by completing four specific aims: 1. Children and young adolescents with autism (n=86) will be randomized to atomoxetine or placebo for 8 weeks to determine its short-term efficacy over the course of an 8-week double-blind study. 2. Responders to atomoxetine will be followed for an additional 10 months of treatment to determine whether response is maintained. 3. A number of important adverse events (e.g., irritability) and health parameters will be monitored over the short- and longer-term studies. 4. Genetic polymorphisms of the cytochrome P450 2D6 gene will be analyzed to determine their relationship to response and tolerability to atomoxetine. When this study is complete, it will be the first to analyze both the efficacy of atomoxetine along with pharmacogenetic data in children and adolescents with autism. Relevance: In this project, we will examine the efficacy of atomoxetine for hyperactivity associated with autism. This research addresses one of the greatest public health needs in mental health today which is finding safer and more effective medical treatments for autism. This research is also unique in its plan to identify genetic predictors of response to drug treatment in autism.